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β-amino acids and carbonyl compounds
Xuan Chen
To cite this version:
Xuan Chen. Applications of radical reactions for the synthesis of β-amino acids and carbonyl com-pounds. Organic chemistry. Institut Polytechnique de Paris, 2020. English. �NNT : 2020IPPAX042�. �tel-02983194�
Applications of radical reactions for
the synthesis of β-amino acids and
carbonyl compounds
Thèse de doctorat de l’Institut Polytechnique de Paris
préparée à École Polytechnique
École doctorale n°626 Ecole Doctorale de l’Institut Polytechnique de
Paris (ED IP Paris)
Spécialité de doctorat: ChimieThèse présentée et soutenue à Palaiseau, le 15 Septembre 2020, par
M. Xuan CHEN
Composition du Jury : Isabelle GILLAIZEAU
Professeur, Université d'Orléans (UMR 7311) Présidente
Luc NEUVILLE
Docteur, University Paris-Saclay Rapporteur
Benoît CROUSSE
Docteur, University Paris-Sud (UMR 8076) Rapporteur
Samir Z. ZARD
Professeur, Ecole Polytechnique (UMR 7652) Examinateur, Directeur de thèse
NNT
:
20
20
IPP
AX
042
I
II
First of all, I am going to express my gratitude to my supervisor Professor Samir Z. Zard who gave me an opportunity to learn in a top university of the world and guided me on the right pathway in my academic career. I still remember the first day that I went to his office, he taught me the basic principle of xanthate chemistry and outlined the research topics in the next three years with profound knowledge. From that time, I changed my view on radical chemistry and realized xanthate transfer process is a powerful tool in organic synthesis. He not only gave me many helps in my research and daily life but also taught me the philosophy of life, the word “you should happy for your success, but more importantly, you should learn from your failure” impressed me the most. I really appreciate everything that he did for me and it is a great honor to work as his Ph.D student.
I would like to thank all the members of jury committee, Prof. Isabelle Gillaizeau, Dr. Luc Neuville and Dr. Benoît Crousse for your precious time to evaluate this manuscript and come to my defense. Thank you for your suggestions.
I want to thank Dr. Alexis Archambeau and Dr. Sébastien Prévost who have made great efforts on the problem sessions part, it is helpful to me and push me forward, I learned a lot from these exercises during the three years.
My special thanks to Dr. Qi HUANG, a former Ph.D student in LSO. He gave me countless help at the beginning of my abroad life, both in my research projects and some trivial personal things and taking time to read and correct this manuscript. The two years we shared is unforgettable in my life.
I also want to thank Vincent R. and Richard L. for providing me many solutions to the problem I encountered in my experiments and gave me some practical tips in my research projects. And also thank them for reading and correction of this manuscript. I would like to thank all of the LSO members: Dr. Yvan, Dr. Bastien Nay, Antoine, Anaïs, Wei, Oscar, Quentin, Gabriela, Dung, Xianzhu, Jean, Benjamin, Valentin, Nicolas, Paula, Cristina, Thomas, Kieu, Eloi, Pjotr. And also express my grateful to Julien for his warm help in many administrative matters and Vincent L. for HRMS analysis.
I would like to thank my family, relatives and friends, they always stand behind me and help me to achieve the goals. I express my deepest gratitude to my parents and my wife for their support. Finally, I especially want to thank my little daughter, her cute face and sweet smile give me the courage and confidence to overcome any difficulties I encountered, and bring me a joyful life.
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Acknowledgements ... I Abbreviations ... VII Avant-Propos ... IX General introduction ... XII
Chapter 1 Introduction to radical chemistry ... 1
1.1 Introduction ... 2
1.2 Physical properties of radicals ... 2
1.2.1 The geometry: planar or pyramidal? ... 2
1.2.2 Radical stability ... 3
1.3 Chemical properties of radicals ... 5
1.3.1 Thermal cleavage ... 5
1.3.2 Photochemical cleavage ... 6
1.3.3 Radicals arising from organoboranes ... 7
1.3.4 Radicals generated by single electron transfer process (SET) ... 8
1.4 Radical reactions ... 8
1.4.1 Radical chain reactions ... 8
1.4.2 Hydrogen abstraction ... 9
1.4.3 Addition to unsaturated bonds ... 10
1.4.4 Fragmentation ... 10
1.4.5 Rearrangement ... 11
1.4.6 Radical Oxidation ... 11
1.5 Conclusion ... 12
Chapter 2 Xanthate based radical chemistry ... 15
2.1 Introduction ... 16
2.2 The Barton-McCombie deoxygenation ... 16
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2.2.2 The mechanism ... 17
2.2.3 Applications ... 17
2.3 Development of the Barton-McCombie deoxygenation ... 18
2.4 Radicals generation from carbon-sulfur bond disconnection: the degenerate transfer of xanthates ... 20
2.5 Preparation of xanthates ... 22
2.5.1 By a simple substitution ... 22
2.5.2 Using a radical procedure ... 23
2.5.3 Other radical approaches ... 24
2.6 Applications of xanthate chemistry ... 25
2.6.1 Applications of radical additions to the synthesis of ketones ... 25
2.6.2 Formation of cyclopropanes ... 27
2.6.3 The xanthate route to amines and anilines ... 28
2.6.4 Stabilization of Radicals by Imides. ... 30
2.6.5 Synthesis of protected amino acid derivatives ... 31
2.6.6 Modification of heterocycles ... 32
2.7 Conclusion ... 36
Chapter 3 A Convergent Route to β-Amino Acids and β-Heteroarylethylamines. An Unexpected Vinylation Reaction ... 41
3.1 Introduction ... 42
3.2 Synthetic routes to β-amino acids ... 42
3.2.1 Arndt–Eistert homologation of α-amino acids ... 42
3.2.2 Mannich-type reaction ... 44
3.2.3 Conjugated addition to α, β-unsaturated carbonyl compounds ... 48
3.2.4 Radical approaches to β-amino acids ... 50
3.3 The xanthate route to β2‑amino acids and to β‑heteroarylethylamines ... 51
3.3.1 Preliminary experiments ... 52
3.3.2 Scope of the xanthate route to β2-amino acid derivatives ... 53
3.3.3 Synthesis of N-protected heteroarylethylamines ... 56
VI
3.4 Conclusion and perspective ... 58
Chapter 4 Application of radical reactions for the synthesis of ketones ... 65
4.1 Introduction ... 66
4.2 Ionic methods in the synthesis of ketones and other carbonyl derivatives ... 67
4.2.1 Alkylation of enolates ... 67
4.2.2 Stork enamine alkylation ... 69
4.2.3 Alkylation of silyl enol ethers ... 71
4.2.4 The Enders SAMP/RAMP hydrazone alkylation. ... 73
4.2.5 Borrowing Hydrogen (BH) strategy for ketone alkylation ... 74
4.3 Radical routes to ketones ... 76
4.3.1 The xanthate transfer process in the synthesis of acyclic ketones ... 79
4.3.2 The vicinal dialkylation of enones by ionic and radical reactions ... 82
4.3.3 Alkylation of esters ... 86
4.4 Conclusion and perspective ... 89
Experimental part ... 98
Molecules of chapter 3 ... 99
Molecules of chapter 4 ... 100
General Experimental Methods ... 102
Experimental Procedures and Spectroscopic Data... 103
Chapter 3 ... 103
VII
Abbreviations
Ac acetyl AIBN azobisisobutyronitrile Ar aryl Boc tert-butyloxycarbonyl Bu butyl t-Bu tert-butyl Bn benzyl Bz benzoyl Cbz carboxybenzyl Cat. catalyst DCE 1,2-dichloroethane DCM dichloromethane DLP dilauroyl peroxide DMF N, N-dimethylformamide dppm bis(diphenylphosphino)methane DTBP di-tert-butyl peroxide EA ethyl acetate EP petroleum ether Et ethyl HMDS bis(trimethylsilyl)amineLDA lithium diisopropylamide
Me methyl Ms methanesulfonyl NBS N-bromosuccinimide NMP N-methyl-2-pyrrolidone NPhth phthalimide Piv pivalate Ph phenyl PhCl chlorobenzene Pr propyl i-Pr iso-propyl
PTSA p-toluenesulfonic acid
Py pyridine TEA triethylamine Tf trifluoromethanesulfonyl THF tetrahydrofuran TMS trimethylsilyl Ts p-toluenesulfonyl Xa O-ethyl xanthate Stoich. stoichiometric
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DNA deoxyribonucleic acid
ESR electron spin resonance
HOMO highest occupied molecular orbital
IR infrared
LUMO lowest unoccupied molecular orbital
NMR nuclear magnetic resonance
Nu nucleophile
RNA ribonucleic acid
SOMO singly occupied molecular orbital
℃ degree Celsius
eq. equivalent
Hz hertz
h hour
min minute
M mole per liter
ppm parts per million
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Dans cette thèse, nous nous concentrons sur l'application de la chimie des radicaux issus des xanthates pour la synthèse de cétones, d'esters et de dérivés d'acides aminés β2. Cette recherche surmonte de nombreux inconvénients associés à l'alkylation des cétones et des esters lors de l'utilisation de méthodes basées sur l'énolate, et complète la dialkylation des cétones insaturées. Le processus de transfert de xanthate offre également une voie convergente vers des acides aminés potentiellement bioactifs. Ces études ont été réalisées sous la direction du Prof. Samir Z. Zard au Laboratoire de Synthèse Organique de l'Ecole Polytechnique. Ce manuscrit comprend quatre chapitres et une partie expérimentale.
Dans le chapitre 1, les aspects généraux de la chimie radicalaire sont brièvement présentés, y compris les propriétés physiques et chimiques des radicaux, les méthodes de génération de radicaux et les types de réactions radicalaires, ainsi que les mécanismes des réactions radicalaires.
Dans le chapitre 2, le mécanisme général et le développement de la désoxygénation de Barton-McCombie sont discutés, suivis de la découverte du transfert dégénératif du xanthate et de ses applications dans la synthèse de divers composés hautement fonctionnalisés ; le groupe fonctionnel pouvant être présent dans le xanthate ou dans l'alcène.
Dans le chapitre 3, nous résumons tout d'abord l'utilité et les stratégies de synthèse vis-à-vis des acides aminés, puis nous décrivons une voie convergente vers les dérivés d'acides aminés β2 en adoptant le processus de transfert du xanthate. Le xanthate peut porter soit un ester, soit un groupe acide carboxylique libre. Lorsque l'α-xanthyl-β-amino ester est utilisé comme xanthate de départ, presque toutes les réactions ont été effectuées sans solvant et ont fourni les produits d'addition souhaités avec un rendement bon à excellent. Lorsque le xanthate portait un groupe acide libre, l'addition sur des hétérocycles était accompagnée d'une décarboxylation spontanée pour donner des hétéroaryléthylamines N-protégées. Dans certains cas, des produits vinyliques inattendus se sont formés et un mécanisme plausible est discuté.
Une voie convergente vers les acides aminés β2 et les hétéroaryléthylamines N-protégées
Dans le chapitre 4, nous présentons brièvement les méthodes précédemment décrites pour l'alkylation des cétones, puis passons à nos propres recherches. En remplaçant les énolates et équivalents d'énolates par des radicaux α-cétonyle, de nombreux inconvénients de l'alkylation des cétones tels que la condensation des aldols, le manque de régiosélectivité, la O-alkylation et la polyalkylation peuvent être minimisés. Ensuite, nous nous concentrons sur la dialkylation
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des cétones α, β-insaturées. Contrairement aux méthodes ioniques traditionnelles qui doivent utiliser des organocuprates et des halogénures d'alkyle, notre nouvelle méthode intègre à la fois des processus ioniques et radicalaires qui évitent l'utilisation des agents organométalliques et des halogénures d'alkyle. Il est à noter que l'étape d'addition de Michael a été significativement affectée par l’encombrement stérique tandis que l'étape d'addition radicalaire a été peu affectée. Sur la base de cette méthodologie, diverses cyclopentanones dialkylées ont été rapidement synthétisées, y compris des composés polycycliques qui sont couramment présents dans les produits naturels. Enfin, afin de généraliser l'alkylation des composés carbonylés, l'α-alkylation des esters a également été étudiée. Dans la section d'extension de portée, nous testons les ajouts radicaux à différents alcènes fonctionnalisés. Toutes les réactions se sont déroulées sans difficultés et présentent une large tolérance de groupe fonctionnel. Des réactions utilisant des lactones comme substrats ont également été réalisées dans les mêmes conditions et se sont avérées tout aussi efficaces.
Application de xanthate à la synthèse de composés carbonylés
En résumé, nous avons utilisé ce processus de transfert de xanthate comme un outil puissant pour synthétiser de nombreux cétones, esters et dérivés d'acides aminés utiles. Cette méthode sans métal présente des conditions de réaction douces, une excellente compatibilité des groupes fonctionnels et une bonne diversité de substrats qui, selon nous, seront particulièrement utiles dans la fonctionnalisation à un stade avancé des produits naturels et pharmaceutiques.
Dans la section expérimentale, les synthèses des 79 produits dans les deux chapitres précédents sont décrite ainsi que leur caractérisation par RMN 1H, RMN 13C, IR, HRMS et points de fusion (lorsque cela est possible).
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In this thesis, we focus on the application of xanthate based radical chemistry for the synthesis of ketones, esters and β2-amino acids derivatives. This research overcomes many drawbacks associated with the alkylation of ketones and esters when using enolate based methods, and complements the dialkylation of unsaturated ketones. The xanthate transfer process also offers a convergent route to potential bioactive amino acids. These studies were accomplished under the guidance of Prof. Samir Z. Zard in the Laboratoire de Synthèse Organique in Ecole Polytechnique. This manuscript consists of four chapters and an experimental part.
In chapter 1, general aspects of radical chemistry are briefly presented, including physical and chemical properties of radicals, methods for radical generation and types of radical reactions, as well as mechanisms of radical reactions.
In chapter 2, the general mechanism and development of the Barton-McCombie deoxygenation is discussed, followed by the discovery of degenerative transfer of the xanthate and the applications in the synthesis of various highly functionalized compounds. Functional group can be present in the xanthate or in the alkene.
In chapter 3, we firstly summarize the utility and synthetic strategies towards amino acids, then we describe a convergent route to β2-amino acids derivatives by adopting the xanthate transfer process. The xanthate can bear either an ester or a free carboxylic acid group. When the α-xanthyl-β-amino ester is used as the starting xanthate, almost all the reactions were performed neat and provided the desired adducts in good to excellent yield. When the xanthate was bearing a free acid group, the addition to hetero-rings was accompanied by spontaneous decarboxylation to afford the N-protected heteroarylethylamines. In some cases, unexpected vinyl products were formed and a plausible mechanism is discussed.
A convergent route to β2-amino acids and N-protected heteroarylethylamines
In chapter 4, we briefly introduce the previously reported methods for the alkylation of ketones, and then move on to our own research. By replacing enolates and enolate equivalents with α-ketonyl radicals, many disadvantages of alkylation of ketones such as aldol condensation, lack of regioselectivity, O-alkylation and polyalkylation can be minimized. Then we focus on the dialkylation of α, β-unsaturated ketones. In contrast with traditional ionic methods which have to use organocopper and alkyl halides, our new method incorporates both ionic and radical processes which avoids the use of aforementioned organometallic
XIV
agents and alkyl halides. It is noteworthy that the Michael addition step was significantly affected by steric hinderance while the radical addition step was little affected. Based on this methodology, various dialkylated cyclopentanones were rapidly synthesized including ring-fused compounds which are commonly present in natural products. Finally, in order to generalize the alkylation of carbonyl compounds, α-alkylation of esters was also investigated. In the scope extension section, we test the radical additions to different functionalized alkenes. All reactions proceeded smoothly and show a broad functional group tolerance. Reactions using lactones as substrates were also performed with the same conditions and were shown to be equally efficient.
Application of xanthate to synthesis of carbonyl compounds
In summary, we used this xanthate transfer process as a powerful tool to synthesize many useful ketones, esters and amino acid derivatives. This metal-free method features mild reaction conditions, excellent functional group compatibility and good substrate scope which we anticipate will be especially useful in the late-stage functionalization of natural products and drugs.
In the experimental section, the syntheses of the 79 products in previous two chapters are described as well as their characterization by 1H NMR, 13C NMR, IR, HRMS, and melting points, when applicable.
1
2
1.1 Introduction
This section will give an overview of radical properties with respect to both physical and chemical properties in order to understand the processes of radical transformation. A free radical is defined as a specie that contains one unpaired electron. It has been 120 years since the first persistent radical (triphenylmethyl radical) was described in 1900 by Moses Gomberg.1 Although the original suggested structure (Ⅰ-1a) of triphenylmethyl dimer was proved to be incorrect by NMR in 1970,2 it aroused more and more attentions in the context of radical transformations. It is now very clear that steric hindrance of triphenylmethyl radical prevents the formation of structure (Ⅰ-1a). Therefore, the unpaired electron has to delocalize from the tertiary carbon to the benzene carbon and then interact with the original radical to form the dimer (Ⅰ-1b) (Scheme 1.1).
Scheme 1.1 Formation of triphenylmethyl radical and dimerization
1.2 Physical properties of radicals
1.2.1 The geometry: planar or pyramidal?
Carbocations have generally planar structures and unstabilized carbanions have pyramidal structures because of the different molecular orbital hybridizations. Radicals have two extreme options. In the first, the carbon center connects three other atoms in a plane and the unpaired electron occupies an empty p orbital. In the second, the unpaired electron is in an sp3 orbital. In this case, the structure would be pyramidal. ESR spectra,3 gas-phase infrared spectroscopy,4 and complementary matrix isolation studies5-6 indicate that the methyl radical is planar, that is a π radical; the methyl must therefore be sp2 hybridized with the unpaired electron in a p orbital. The geometry and energy level diagram is depicted below (Figure 1.1).
3
Figure 1.1 Geometry and energy level diagram of methyl radical
Since the barrier of inversion is very small, simple alkyl radicals are tend to be slightly pyramidal. The more hindered substituents attached to the radical carbon, the more pyramidal the radical is (ethyl<i-propyl<t-butyl). Note that the degree of pyramidalization of the t-butyl radical is approximately 40% that of a perfect tetrahedron, and it has a barrier to inversion on the order of 1 kcal/mol.7 There is another situation when the radical carbon is connected to very electronegative atoms (e.g., CF3). In this case, the radical will prefer a pyramidal shape,8 i.e. increasing the electronegativity increases the deviation from planarity.9
Figure 1.2 Geometry of substituted alkyl radicals10
1.2.2 Radical stability
The bond dissociation energy can give a guide to the ease of which kind of radicals can form and also indirectly show their stability (Table 1.1).11 A conclusion can be made: the order of stability of radicals is tertiary > secondary >primary, and benzyl radicals, allyl radicals are more stable than alkyl radicals. These observations can be explained by π-delocalization and hyperconjugation.12 Furthermore, alkyl radicals (even tertiary radicals) are less stable than those radicals which are adjacent to carbonyl or ether groups, or radicals centered on a carbonyl carbon atom.
Table 1.1 Dissociation energy of various C-H bonds C-H bonds Dissociation
energy, kJ mol−1 C-H bonds
Dissociation energy, kJ mol−1
CH3-H (methyl) 439 HC≡C-H (alkynyl) 544
4
MeCH2-H (primary) 423 MeCOCH2-H 385
Me2CH-H (secondary) 410 H2C=CH2CH2-H (allyl) 364
RC(=O)-H (acyl) 364 Me3C-H (tertiary) 397
PhCH2-H (benzyl) 372 Ph-H (phenyl) 464
(i) Radical stabilized by electron-withdrawing groups
The unpaired electron usually occupies a p orbital (SOMO orbital), while electron-withdrawing groups like carbonyl and nitrile have a low-lying empty π* orbital. By combining the two orbitals (p and π* orbital), two new orbitals are generated according to Molecular Orbital Theory. Now, the unpaired electron occupies the new lower-energy SOMO, which therefore lowers the total energy of the molecule. The unpaired electron decreases in energy and is so-called electrophilic in character (Figure 1.3).
Figure 1.3 Radical stabilized by electron-withdrawing groups (ii) Radical stabilized by electron-donating groups
Similarly, when combining the relatively high-energy and fully occupied n orbitals of an electron-donating group (taking an alkoxyl group as an example) with an occupied p orbital of a radical (radical SOMO orbital), again, two new molecular orbitals are formed. Two paired electrons will fill the newly formed lower-energy orbital and one electron will occupy the newly formed SOMO orbital, which will have a higher energy than the old SOMO. Although the single electron now occupies a higher-energy SOMO orbital, the other paired electrons occupy a lower-energy orbital which has a net effect of lowering the overall energy (Figure 1.4).
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Figure 1.4 Radical stabilized by electron-donating groups (iii) Radical kinetically stabilized by stereochemistry
Electronic effects and steric hindrance also play a crucial role in the kinetic stability of radicals. The observation that both phenyl and t-butyl substituted phenoxy radicals 1 are persistent, which means the steric effects probably dominate. Some crowded alkyl radicals like 2-4 do not dimerize. Thus, while steric effects do not thermodynamically stabilize a radical, they can modify considerably its kinetic stability. (Figure 1.5).13
Figure 1.5 Radical stabilized by steric hinderance
1.3 Chemical properties of radicals
Free radicals arise from the homolytic cleavage of a chemical bond so that each part keeps one electron. Generally speaking, the energy to sever a chemical bond can be supplied by two methods: thermally and photochemically.
1.3.1 Thermal cleavage
Heating organic molecules at a high enough temperature in the gas phase can produce free radicals. Organic peroxides and aliphatic azo compounds are frequently used sources to generate radicals in a by thermal decomposition. Two radicals can be formed by the cleavage of an O-O bond of an organic peroxide (eq a. in Scheme 1.2). For diacyl peroxides, the radicals formed will decarboxylate and give alkyl radicals (eq b. in Scheme 1.2). Cleavage of two C-N
6
bonds on an azo compound will release one molecule nitrogen and afford two alkyl radicals (eq c. in Scheme 1.2).
Scheme 1.2 Formation of radicals by thermal cleavage of chemical bond
1.3.2 Photochemical cleavage
The energy of visible light energy ranges from 167–293 kJ/mol and the energy of ultraviolet light is approximately 586 kJ/ mol. The energies of some covalent single bonds are also known and are of the same order of magnitude (Table 1.2).14-16 Treatment these chemical bonds with visible or UV light will homolytically cleave the covalent bonds when the light has an energy of the same order of magnitude of the covalent bond.
Table 1.2 Energies of some covalent single bonds
Bond type Energy
(kJ/mol) Corresponding wavelength (nm) C-H 397 301 C-O 368 325 C-C 347 345 C-S 255 470 C-Br 275 436 O-O 159 755 Cl-Cl 243 495
In 1992, Courtneidge reported the photo-induced generation of alkoxyl radicals upon the irradiation of cyclopentanol in the presence of mercuric oxide and iodine (Scheme 1.3).17
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Scheme 1.3 Formation of alkoxyl radicals by photolysis
Another efficient and selective approach to generate alkoxy radicals by homolytic dissociation of O-S bond was developed by Pasto and co-workers in 1994. (Scheme 1.4).18
Scheme 1.4 Photochemical cleavage of O-S bond to form alkyl radicals
In 1994, the Cossy group reported the generation of alkyl radicals by irradiating alkyl halides at 254 nm in the presence of triethylamine (Scheme 1.5).19
Scheme 1.5 homolytic cleavage of C-X bond
The hydroxyl radical (HO•) is a widely used oxygen centered reactive intermediate in both biological and environmental processes. Homolysis of N-hydroxypyridin-2-thione(Ⅰ-8) was achieved with a laser flash (Nd:YAG laser, nominal pulse width =10 ns) in acetonitrile, which afforded the hydroxyl radical and the pyrithiyl radical(Ⅰ-9) (Scheme 1.6).20
Scheme 1.6 Hydroxyl radical generated by laser flash
1.3.3 Radicals arising from organoboranes
The so-called SH2 reaction (second-order homolytic displacement) is a substitution of an alkyl group of a trialkyl borane with triplet diradical oxygen. In this process, the oxygen enters the unoccupied p orbital of the trigonal borane while displacing one of the alkyl radicals. (Scheme 1.7).21
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Scheme 1.7 Borane as a source of radicals
1.3.4 Radicals generated by single electron transfer process (SET)
Alkali metals such as sodium, lithium or potassium when dissolved in liquid ammonia can serve as reducing reagents in the Birch reduction. In fact, sodium and liquid ammonia exist as the electride salt form ([Na(NH3)x]+ e−), which means the single electron is solvated and standing by to add onto the aromatic ring to give the corresponding radical anion (Scheme 1.8).Scheme 1.8 Radical generation by single electron transfer process
1.4 Radical reactions
1.4.1 Radical chain reactions
The radical chain process involves three steps: initiation, propagation and termination. (i) Initiation: Organic peroxides or other azo compounds can act as initiators and can be thermally or photochemically cleaved to form two radicals. This is followed by an interaction with one of the starting materials to generate a new radical for the further transformation (Scheme 1.9).
Scheme 1.9 Initiation of chain reaction
(ii) Propagation: in this step, the radical X• which arises from starting material Y-X will be trapped by an unsaturated bond, for example an alkene, which in turn generates a new carbon-centered radical. This newly formed radical reacts with Y-X to form the final addition product and regenerate X•, and thus propagate the chain. (Scheme 1.10) In principle, only one molecule
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of initiator is necessary (actually, sub-stoichiometric quantities, about 10 mol% are needed) for the reaction to reach completion.
Scheme 1.10 Propagation of chain reaction
(iii) Termination: When two free radicals react with each other, a stable and non-reactive adduct is formed. Although this process decreases the overall energy, it rarely happens because of the low concentration of radical species. Nevertheless, these termination reactions stop the chain and more initiator has to be added (Scheme 1.11).
Scheme 1.11 Termination of chain reaction
1.4.2 Hydrogen abstraction
The process of abstraction involves a radical reacting with another molecule to abstract a hydrogen atom, or the hydrogen atom is transferred in an intramolecular process. An example of this process is the abstraction of a hydrogen atom from water, mediated by TiIII complexes (Ⅰ-10) (Scheme 1.12).22
Scheme 1.12 Water acts as hydrogen source
In a radical chain polymerization reaction, there can be hundreds or thousands of propagation steps between initiation and termination steps. However, for the synthesis of small molecules far fewer propagation steps are used and often employ tributyltin hydride to reduce the carbon-centered radical by an atom-transfer reaction. In this process, the alkyl radical can abstract a hydrogen from n-Bu3SnH to provide alkane and a new radical n-Bu3Sn•. Tin radicals react with each other tin radical to give (n-Bu3Sn)2, which constitutes one of the possible termination steps (Scheme 1.13).
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Scheme 1.13 Tributyltin hydride as hydrogen source
1.4.3 Addition to unsaturated bonds
Addition to alkenes and alkynes can be intra- or intermolecular. The initially formed radical can be trapped by an internal double bond to produce a cyclic product. In the formation of bicyclic rings reaction, the ratio of six-membered ring product Ⅰ-14a and five-membered ring product Ⅰ-14b is approximately 1:2 (Scheme 1.14). This means even if a six-membered ring is more stable, the formation of a five-membered ring is faster. The product distribution depends on the length of the chain connecting the radical and olefinic centers.23
Scheme 1.14 Radical addition to form cyclic compounds
The propagation in a radical chain reaction we mentioned above involves a radical addition to a double bond. If the newly formed radical adds to another alkene molecule, a dimer is formed, and this second radical can add to the third molecule of alkene, and so on, until the chain process terminated by other methods. This is the mechanism of free radical polymerization (Scheme 1.15).
Scheme 1.15 Polymerization of alkene
1.4.4 Fragmentation
Fragmentation of radicals can generate a new radical and a new molecule. For example, the reaction of a butanoyl radical with α, α-dimethylallyl phenyl sulfides(Ⅰ-15) provides the radical
11
adduct Ⅰ-16, which undergoes a β-elimination to afford a thiyl radical and 7-methyloct-6-en-4-one Ⅰ-17. This kind of fragmentation is referred to as β-scission (Scheme 1.16).24
Scheme 1.16 β-scission of radical
1.4.5 Rearrangement
Radical mediated 1,2-rearrangements are much less common than the nucleophilic type rearrangements, but they do occur in a two-step sequence. The neophyl rearrangement for example is a free radical mediated 1,2- migration of an aryl group and the rearrangement occurs via a 1-oxaspiro [2,5] octadienyl radical (Scheme 1.17). The substituent on the ring is crucial to this rearrangement’s rate constant: electron-withdrawing groups can increase the rate constant whereas the electron-donating groups decrease the rate constant.25
Scheme 1.17 Radical rearrangement
1.4.6 Radical Oxidation
Oxidation takes place when radicals lose one electron to metal ions. Alkyl radicals have two pathways: oxidative elimination and oxidative substitution (Scheme 1.18).
Scheme 1.18 Radical oxidation
In some cases, the metal acts as not only oxidant but also as an initiator for a radical process. For example, t-butyl peracetate can be cleaved by Cu(Ⅰ) to form a Cu(Ⅱ)OAc and a t-butoxy
12
radical which then abstracts a hydrogen from an alkane to generate an alkyl radical which undergoes oxidation by Cu(Ⅱ) to give Cu(Ⅰ) species and the corresponding acetoxy alkane (Scheme 1.19).26
Scheme 1.19 Copper initiated and oxidized radical reaction
1.5 Conclusion
Interest in free radicals over the past decades has increased as their crucial role in both chemistry and biology has come to light. In this chapter, the physical property of free radicals was briefly discussed both in geometry and stability aspects. Meanwhile, the radical generation methods and some fundamental radical reactions were particularly emphasized not only by general principle description but also some practical examples. However, free radical intermediates are involved in many reactions in organic synthesis - too many to list and therefore this brief introduction is just a glance at free radical chemistry.
13
1. Gomberg, M., An instance of trivalent carbon: Triphenylmethyl. J. Am. Chem. Soc. 1900, 22, 757. 2. Lankamp, H.; Nauta, W. T.; MacLean, C., A new interpretation of the monomer-dimer equilibrium of
triphenylmethyl- and alkylsubstituted-diphenyl methyl-radicals in solution. Tetrahedron Lett. 1968,
9, 249.
3. Fessenden, R. W., Electron spin resonance spectra of some isotopically substituted hydrocarbon radicals. J. Phys. Chem. 1967, 71, 74.
4. Tan, L. Y.; Winer, A. M.; Pimentel, G. C., Infrared Spectrum of Gaseous Methyl Radical by Rapid Scan Spectroscopy. J. Chem. Phys. 1972, 57, 4028.
5. Jacox, M. E., Matrix isolation study of the infrared spectrum and structure of the CH3 free radical. J.
Mol. Spectrosc. 1977, 66, 272.
6. Pacansky, J.; Bargon, J., Low temperature photochemical studies on acetyl benzoyl peroxide. Observation of methyl and phenyl radicals by matrix isolation infrared spectroscopy. J. Am. Chem.
Soc. 1975, 97, 6896.
7. Paddon-Row, M. N.; Houk, K. N., Origin of the pyramidalization of the tert-butyl radical. J. Am.
Chem. Soc. 1981, 103, 5046.
8. Bernardi, F.; Cherry, W.; Shaik, S.; Epiotis, N. D., Structure of fluoromethyl radicals. Conjugative and inductive effects. J. Am. Chem. Soc. 1978, 100, 1352.
9. Chen, K. S.; Tang, D. Y. H.; Montgomery, L. K.; Kochi, J. K., Rearrangements and conformations of chloroalkyl radicals by electron spin resonance. J. Am. Chem. Soc. 1974, 96, 2201.
10. Carey, F. A.; Sundberg, R. J., Advanced organic chemistry. Part A: Structure and Mechanisms. 2007. 11. Jonathan Clayden, N. G., Stuart Warren, Organic Chemistry. Organic Chemistry, 2nd edition 2012. 12. Sustmann, R.; Korth, H.-G., The Captodative Effect. In Adv. Phys. Org. Chem., Bethell, D., Ed.
Academic Press: 1990; Vol. 26, pp 131.
13.Rüchardt, C. In Steric effects in free radical chemistry, Berlin, Heidelberg, Springer Berlin Heidelberg: Berlin, Heidelberg, 1980; pp 1.
14. Grelbig, T.; Pötter, B.; Seppelt, K., Die Stärke von Schwefel-Kohlenstoff-Mehrfachbindungen. Chem.
Ber. 1987, 120, 815.
15. Lovering, E. G.; Laidler, K. J., A system of molecular thermochemistry for organic gases and liquids: part ii. extension to compounds containing sulphur and oxygen. Can. J. Chem. 1960, 38, 2367. 16. D F McMillen, a.; Golden, D. M., Hydrocarbon Bond Dissociation Energies. Annu. Rev. Phys. Chem.
1982, 33, 493.
17. Courtneidge, J. L., Alkoxyl radicals from alcohols I. The hypoiodite reaction of cyclopentanol: evidence for sequential rather than competitive reaction pathways. Tetrahedron Lett. 1992, 33, 3053.
14
18. Pasto, D. J.; Cottard, F., Demonstration of the synthetic utility of the generation of alkoxy radicals by the photo-induced homolytic dissociation of alkyl 4-nitrobenzenesulfenates. Tetrahedron Lett. 1994,
35, 4303.
19. Cossy, J.; Ranaivosata, J.-L.; Bellosta, V., Formation of radicals by irradiation of alkyl halides in the presence of triethylamine. Tetrahedron Lett. 1994, 35, 8161.
20. DeMatteo, M. P.; Poole, J. S.; Shi, X.; Sachdeva, R.; Hatcher, P. G.; Hadad, C. M.; Platz, M. S., On the Electrophilicity of Hydroxyl Radical: A Laser Flash Photolysis and Computational Study. J. Am.
Chem. Soc. 2005, 127, 7094.
21. Ollivier, C.; Renaud, P., Organoboranes as a Source of Radicals. Chem. Rev. 2001, 101, 3415. 22. Cuerva, J. M.; Campaña, A. G.; Justicia, J.; Rosales, A.; Oller-López, J. L.; Robles, R.; Cárdenas, D.
J.; Buñuel, E.; Oltra, J. E., Water: The Ideal Hydrogen-Atom Source in Free-Radical Chemistry Mediated by TiIII and Other Single-Electron-Transfer Metals? Angew. Chem. Int. Ed. 2006, 45, 5522. 23. Burnett, D. A.; Choi, J. K.; Hart, D. J.; Tsai, Y. M., Pyrrolizidinone and indolizidinone synthesis: generation and intramolecular addition of .alpha.-acylamino radicals to olefins and allenes. J. Am.
Chem. Soc. 1984, 106, 8201.
24. Lewis, S. N.; Miller, J. J.; Winstein, S., 1,2-Migrations in alkyl radicals. J. Org. Chem. 1972, 37, 1478. 25. Aureliano Antunes, C. S.; Bietti, M.; Ercolani, G.; Lanzalunga, O.; Salamone, M., The Effect of Ring Substitution on the O-Neophyl Rearrangement of 1,1-Diarylalkoxyl Radicals. A Product and Time-Resolved Kinetic Study. J. Org. Chem. 2005, 70, 3884.
26. Kochi, J. K.; Mains, H. E., Studies on the Mechanism of the Reaction of Peroxides and Alkenes with Copper Salts*,1. J. Org. Chem. 1965, 30, 1862.
15
16
2.1 Introduction
Many xanthate salts are yellow, hence their Greek name 'xanthos' meaning "yellowish, golden. The term xanthate usually refers to a salt with the formula ROCS2−M+ where R is an alkyl group and the metal ion is potassium or sodium ion. Although it has been 198 years since xanthate salts were discovered by Danish chemist William Christopher Zeise,1 the utility of xanthate in chemistry remained largely unexplored until 1899,when a xanthate reaction was reported for the first time in a pyrolysis process by L. Chugaev. 2-3 The xanthate group arises from the corresponding alcohols Ⅱ-1 (1°, 2°, and 3°) and then undergoes a unimolecular elimination to afford desired alkene Ⅱ-4. The β-hydrogen atom is removed via cis-elimination through a 6-membered cyclic transition state Ⅱ-3. The reaction is especially valuable for the conversion of sensitive alcohols to the corresponding olefins without rearrangement of the carbon skeleton (Scheme 2.1).
Scheme 2.1 Chugaev elimination
2.2 The Barton-McCombie deoxygenation
2.2.1 An overall view: from alcohol to alkane
The Chugaev elimination aroused some interest in xanthate chemistry, but was nevertheless very limited in applications. The discovery of the Barton-McCombie radical deoxygenation4 had a deep influence in organic synthesis. Traditional methods to reduce alcohol derivatives such as tosylate, mesylate, sulphate, or halides using LiAlH4,5 NaBH,6 or metal catalysis7 have limitations when sterically hindered -OH groups are involved since the reactants and intermediates cannot get close to each other. The Barton-McCombie deoxygenation uses widely commercialized and easily handled alcohols as the radical source and is less susceptible to steric factors which means even more sterically hindered secondary and certain tertiary alcohols (tertiary xanthates are very susceptible to the Chugaev elimination) may be reduced by this method.8 In a typical procedure the alcohol Ⅱ-5 is first converted to a xanthate or related derivative Ⅱ-7, which is then exposed to tri-n-butyltin hydride in refluxing toluene to afford the desired alkane Ⅱ-8 (Scheme 2.2).
17
Scheme 2.2 Barton-McCombie deoxygenation
2.2.2 The mechanism
A proposed mechanism of Barton-McCombie deoxygenation is given in Scheme 2.3.9-10 The initiation step involves the thermal homolysis of 2,2'-azobis(iso-butyronitrile) (AIBN) followed by a hydrogen abstraction from tri-n-butyltin hydride. In the propagation step, the formation of a strong tin-sulfur bond drives the tin radical to add reversibly to the carbon-sulfur double bond to form radical Ⅱ-10, which then fragments to radical Ⅱ-12 and byproduct Ⅱ-11. Radical Ⅱ-12 moves one step forward to abstract hydrogen from tri-n-butyltin hydride to complete the overall reaction and regenerate the chain-carrier, tri-n-butyltin radical. However, byproduct Ⅱ-11 has a different fate. It is unstable and decomposes to yield carbonyl sulphide (COS) and tri-n-butyl-stannane (Scheme 2.3).
Scheme 2.3 Proposed mechanism of Barton-McCombie deoxygenation
2.2.3 Applications
Denmark and co-workers developed an asymmetric synthetic route to access pyrrolizidine necine base (-)-hastanecine. The key reaction in the transformation is a sequential inter [4+2]/inter [3+2] cycloaddition.11 After rapidly constructing the desired carbon framework, a late-stage removal of the hydroxyl group was accomplished using the Barton-McCombie deoxygenation procedure (Scheme 2.4).
18
Scheme 2.4 Removal of hydroxyl group in the total synthesis of (-)-Hastanecine
The first total synthesis of penmacric acid and its stereoisomer was reported by Naito's group.12 After the crucial Et
3B-induced stereoselectivity step, the unnecessary hydroxyl group was reduced efficiently by the Barton-McCombie procedure (Scheme 2.5).
Scheme 2.5 Hydroxyl group reduction in total synthesis of Penmacric acid
(-)-Kishi lactam, which is a versatile intermediate to construct perhydrohistrionicotoxin (pHTX) alkaloids, was synthesized by Luzzio's and co-workers.13 Barton-McCombie process was again employed at a late stage to remove one of the secondary hydroxyl groups (Scheme 2.6).
Scheme 2.6 -OH reduction in total synthesis of Penmacric acid
2.3 Development of the Barton-McCombie deoxygenation
Even nowadays, the Barton-McCombie deoxygenation is still a powerful synthetic tool in organic chemistry despite it being more than 40 years since its discovery.14-16 Tri-n-butyltin hydride represents an efficient hydrogen donor in this process because of the relatively weak Sn-H bond strength (74 Kcal/mol),17 but has several drawbacks including toxicity, complicating purifications and in some cases the need for a syringe pump when low concentrations are19
necessary.
To overcome the disadvantages of tin hydride, certain organosilicon hydrides contribute another option in the deoxygenation the process due to the weak Si-H bond strength (79 Kcal/mol). In 1991, Barton's group reported deoxygenation of primary and secondary alcohols with phenylsilane instead of tri-n-butyltin hydride as hydrogen donor. The reaction proceeded efficiently in boiling toluene with good to excellent yields (Scheme 2.7).18
Scheme 2.7 Silanes acting as hydrogen atom donor in deoxygenation
An alternative to the original method of Barton-McCombie deoxygenation was developed by Gregory C. Fu and co-workers which involved a new procedure that can dramatically decrease the amount of tri-n-butyltin hydride from 1.5-3 equiv to 15 mol%.19 In this procedure, the Bu3SnH is a catalyst and polymethylhydrosiloxane (PMHS; TMSO-(SiHMeO)n-TMS) is the stoichiometric reductant (Scheme 2.8).
Scheme 2.8 Bu3SnH catalyzed deoxygenation
Ollivier and co-workers developed a tin-free photoredox procedure to accomplish deoxygenation.20 Activation of the secondary or tertiary alcohol with thiocarbonyl diimidazole (TCDI) provides intermediate Ⅱ-28, which is followed by a visible light photocatalytic reduction procedure in the presence of iridium complex Ir(ppy)3 and N,N-diisopropylethylamine (DIPEA), to provide the desired alkanes Ⅱ-31. This tin-free process proceeds by a SET manner to transfer one electron from the iridium complex to the thiocarbamate precursor to form a thiocarbamate radical anion. This radical anion then collapses to generate a carbon-centered radical which can abstract a hydrogen atom either from the amine radical cation coming from the reduction of iridium catalyst or directly from DIPEA (Scheme 2.9).
20
Scheme 2.9 Proposed mechanism for photocatalytic Barton-McCombie deoxygenation
2.4 Radicals generation from carbon-sulfur bond
disconnection: the degenerate transfer of xanthates
After the explosive growth of deoxygenations with the Barton-McCombie method, chemists uncovered more details about the mechanism. Unlike the originally proposed mechanism, Barker and Beckwith assumed another pathway for the Barton-McCombie deoxygenation,21 whereby the tin radical reacts with the sulfide sulfur of the xanthate Ⅱ-32 to form an alkoxythiocarbonyl radical Ⅱ-33 which releases one molecule carbonyl sulfide to give an R radical. Then the alkyl radical abstracts a hydrogen atom from tri-n-butyltin hydride to afford alkane and stannyl radical to accomplish the chain propagation (Scheme 2.10).
Scheme 2.10 Barker and Beckwith's mechanism of deoxygenation
Barton's group subsequently conducted a series of competition experiments to investigate the mechanistic issues.10, 22 Radical S
H2 reactions are affected by steric hinderance like other bimolecular substitutions. Hence, the idea was to do a comparison between the S-methyl dithiocarbonate Ⅱ-34 and the bulkier isopropyl analogue Ⅱ-35 (Scheme 2.11). If the reduction process was as Barker and Beckwith described, then substrate 34 should react faster than Ⅱ-35 and afford the desired product. But the outcome was surprising: the more hindered xanthate reacted faster than the less hindered one and the S-stannylated xanthate Ⅱ-39 was isolated along with propane as the co-product.
21
Scheme 2.11 General principle for the competition experiment
Two conclusions could be drawn from these observations, summarized in Scheme 2.11: 1. Since carbon radicals also react fast with thiocarbonyl derivatives, it is possible now to write a reaction manifold where an exchange between radicals R• and R1• by an addition-fragmentation (paths A, B in Scheme 2.12); 2. when the newly generated carbon radicals have similar stabilities (cholestanyl and isopropyl radicals in the present case), the weaker C-S bond cleavage is favored over the cleavage of the C-O bond (Scheme 2.12).
Scheme 2.12 Possible fragmentation of xanthate radical
Based on these facts, a large amount of work has been done in the past three decades in the Zard group 23-26 to investigate the disconnection of a carbon-sulfur bond in xanthates to participate in a general radical-chain process. To understand the transformation, a simplified mechanism is shown below (Scheme 2.13).
22
Scheme 2.13 Simplified mechanism for the addition of xanthates to alkenes
1.) The initiation step is the homolytic cleavage of the dilauroyl peroxide (DLP) to generate undecyl radicals, which can attack the starting xanthate to provide radical R•. This radical can rapidly react with its precursor, xanthate Ⅱ-41, to form a stabilized radical Ⅱ-46. Radical Ⅱ-46 is a hindered but stabilized radical that interacts only slowly with other radicals. Besides, it is unable to disproportionate (no β-hydrogens). Therefore, it has to fragment back to radical R•. The equilibrium between radical Ⅱ-46 and radical R• ensures the continuous regeneration of R•, hence considerably increasing its lifetime in the medium. Radical R• can now be trapped by unactivated alkene Ⅱ-42 to provide adduct radical Ⅱ-43, which can react with the starting xanthate 41 to form another dormant radical 44. 2.) Because the active radicals R• and Ⅱ-43 are mostly in their dormant state Ⅱ-46 and Ⅱ-44 respectively, their absolute concentration remain very low and unwanted radical−radical interactions are curtailed. 3.) In order to limit oligomerization, R• should be more stable than Ⅱ-43. 4.) If adduct radical Ⅱ-43 is particularly electron-rich, it can be oxidized by the peroxide to give cation Ⅱ-47. This process is particularly useful in cyclizations and intermolecular additions to (hetero)aromatics. The only cost is to use stoichiometric quantities of dilauroyl peroxide.
2.5 Preparation of xanthates
2.5.1 By a simple substitution
Generally, displacement of a leaving group such as a halide or a tosylate by a xanthate salt furnishes the desired xanthate (Scheme 2.14).
23
Scheme 2.14 General xanthate formation method by substitution
2.5.2 Using a radical procedure
The SN2 reaction mentioned above to synthesize xanthate is a quite simple approach but is inefficient with hindered substrates (e.g. tertiary). This limitation can be overcome by radical based approaches. Thus, merely heating a mixture of a tertiary diazo derivative Ⅱ-48 and a bis-xanthate Ⅱ-49 in cyclohexane will give the desired tertiary bis-xanthate Ⅱ-50 (Scheme 2.15).27
Scheme 2.15 Diazo react with dithionodisulfide to form stereo hindered xanthate
The addition of tin radicals onto a xanthate group is a reversible process. It is therefore possible to use S-triphenylstannyl xanthate Ⅱ-52 as a tin radical source which can generate an R• radical from R-X (X represents a group that can be abstracted by tin radicals: bromide, iodide, xanthate). The newly formed alkyl radical can then react with the tin xanthate and by a series of reversible steps give the desired xanthate Ⅱ-53 (Scheme 2.16).28
Scheme 2.16 Reaction of R-X with stannyl xanthate
Acyl radicals can be generated by irradiating S-acyl xanthate Ⅱ-54 with mercury-arc or tungsten lamps. On one hand, the acyl radical Ⅱ-56 can be captured by appropriate olefinic traps but on the other hand it can lose carbon monoxide at an appropriate temperature to give an alkyl radical Ⅱ-57 which can react with xanthate radical Ⅱ-55 to furnish a new S-alkyl xanthate Ⅱ-58 (Scheme 2.17).29
24
Scheme 2.17 Generation of S-alkyl xanthate from S-acyl xanthate
S-Alkoxycarbonyl xanthate Ⅱ-59 is also able to generate alkoxycarbonyl radical Ⅱ-60, and tend to lose carbon dioxide to form radical Ⅱ-61. The radical Ⅱ-61 could react with alkyl radical Ⅱ-62 to give a new xanthate Ⅱ-63 (Scheme 2.18).30
Scheme 2.18 Decarboxylation of S-alkoxycarbonyl xanthate to form alkyl xanthate
2.5.3 Other radical approaches
During the xanthate radical addition, a new xanthate product is formed (Scheme 2.19), and thus constitutes a powerful synthesis of xanthates.
Scheme 2.19 Radical addition to form a new xanthate
In 2016, Alexanian and co-workers developed another radical method to prepare xanthates through aliphatic C−H xanthylation. N-Xanthylamide Ⅱ-64 acts as both hydrogen abstractor and xanthate source in this transformation (Scheme 2.20).31
25
Scheme 2.20 Direct C−H xanthylation
2.6 Applications of xanthate chemistry
The degenerative radical transfer process of xanthate onto unactivated alkenes offers a convenient, efficient, and economical synthetic methodology to rapidly construct richly functionalized compounds. During the past three decades Zard's group has broadly extended the scope of this process in organic synthesis. To date, this transformation not only can be readily applied to access open-chain, cyclic and polycyclic compounds but also it exhibits efficiency in the synthesis or modification of aromatic and heterocyclic compounds.
2.6.1 Applications of radical additions to the synthesis of ketones
The general procedure of regioselective alkylation of carbonyl compounds includes two steps: the first step is the preparation of xanthate from alkyl halides and the second step is a radical addition to alkenes (Scheme 2.21).Scheme 2.21 General procedure for the radical alkylation of carbonyl compounds (i) mono-alkylation of ketone
To functionalize highly base-sensitive α, α-dichloroketones, the 1,1-dichloroacetonyl xanthate Ⅱ-66 has emerged as the appropriate substrate and its radical addition to several olefins proceeded efficiently (Scheme 2.22). Epoxide bearing alkene Ⅱ-67 was well tolerated in this reaction and gave a high yield of adduct Ⅱ-70a. The reaction resulted in an addition−fragmentation product Ⅱ-70b in 89% yield when β-pinene Ⅱ-68 was used as the alkene partner. It should be mentioned that adding xanthate Ⅱ-66 to vinyl pivalate Ⅱ-69 can form a latent aldehyde group Ⅱ-70c. The further transformation of the radical adducts is also synthetically interesting. The xanthate adducts Ⅱ-70d were ozonolyzed, followed by a
26
triethylamine-catalyzed Favorskii rearrangement to give complete selectivity in the formation of the corresponding Z-alkene Ⅱ-71. The newly formed thiocarbonate enones can be further elaborated into the corresponding dienes Ⅱ-72 by exposure to DBU in toluene at ambient temperature.32
Scheme 2.22 Synthesis of Z‑alkenoates and E, E‑dienoates (ii) dialkylation of ketone
The xanthate addition also offers a solution to the synthesis of α, α′-dialkyl unsymmetrical ketones which can be troublesome to construct by the enolate pathway.33 By the exploiting the difference in stability between the secondary radical Ⅱ-75a and primary radical Ⅱ-75c, it is possible to accomplish a sequential regioselective addition to two different alkenes. The dixanthate also shows high reactivity, the yields being 82% and 86% when the addition carried out with ally phthalimide and then with allyltrimethylsilane. The final unsymmetrical α, α′-dialkylated ketone product Ⅱ-75a was obtained in 86% yield by a simple reduction with Barton's hypophosphorus reagent.34-35 The depicted examples of MIDA boronate Ⅱ-75b, malonate Ⅱ-75c further illustrate the functional group tolerance of this chemistry (Scheme 2.23).
27
Scheme 2.23 Synthesis of α, α′ -dialkyl unsymmetrical ketones
2.6.2 Formation of cyclopropanes
The cyclopropane ring is the smallest cyclic structure and constitutes a very attractive building block in organic synthesis. Many cyclopropane natural products show significant biological activity. Besides the Simmons−Smith cyclopropanation and the Johnson–Corey– Chaykovsky reaction, the xanthate based radical addition can also be applied for the synthesis of substituted cyclopropanes.36 Thus, ozonolyzed product 37 Ⅱ-78 exists in an equilibrium with its enolate 79a in the presence of a base and undergoes acyl shift to free thiolate anion Ⅱ-79c. This is trapped by 1,4-dibromobutane to form the corresponding sulfonium salt Ⅱ-79d, which is a good leaving group and reacts as shown in Ⅱ-79e to furnish cyclopropane Ⅱ-80 (Scheme 2.24).
28
Scheme 2.24 The synthesis of triethylsilyl-substituted cyclopropanes
2.6.3 The xanthate route to amines and anilines
The amino group is a fundamental entity in organic chemistry, amines are ubiquitous and can be found in natural products, drug candidates, and polymers.38 The protected amine can be present either on the alkene or on the xanthate partner when taking advantage of the xanthate transfer process for the synthesis of various (protected) amines (Scheme 2.25).
Scheme 2.25 Xanthate route to protected amines
α-Trifluoromethylamine derivatives can be obtained efficiently by adding the corresponding xanthate Ⅱ-81 to various functionalized olefins.39 In the case of adduct Ⅱ-83a, a second addition with allyltrimethylsilane furnishes highly functionalized product Ⅱ-84a in 72% yield. Product Ⅱ-84b bearing two differently protected amino groups was obtained in 78% yield by this tin-free procedure.40 A useful application of xanthate chemistry is the ring-closure onto aromatic rings, as illustrated by the synthesis of indoline Ⅱ-84c. This transformation requires a stoichiometric amount of peroxide, which acts as both as the initiator and as the oxidant for the intermediate cyclohexadienyl radical (not shown) (Scheme 2.26).
29
Scheme 2.26 Xanthate route to protected amines
Protected 1,2-diamines were also readily synthesized by adding various xanthates to N,N′-diacylimidazol-2-one.41 A few examples Ⅱ-87a-d are listed in Scheme 2.27-A to illustrate the formation of masked diamines by the first radical addition. A second addition to unactivated alkenes is possible due to the sufficient stabilization of the adduct radical by the imide group. Reductive dexanthylation using Barton's method finally affords highly functionalized diamines Ⅱ-88. Examples Ⅱ-88a, b illustrate a convenient access to protected triamines (Scheme 2.27-B).
30
2.6.4 Stabilization of Radicals by Imides.
It is worth noting the imide group imparts a non-obvious stabilization of radicals that has been exploited in the xanthate radical addition. Under standard conditions,39 xanthate Ⅱ-89 reacted cleanly with N-vinyl pyrrolidone, while similar reactions with vinyl N-phthalimide gave mostly oligomers 95. In contrast, highly stabilized radical 97 generated from xanthate Ⅱ-96 can be trapped by alkene Ⅱ-90 to furnish adduct Ⅱ-98 cleanly with almost no formation of oligomer (Scheme 2.28).42 According to the mechanism of radical addition (see: Scheme 2.13), the formation of oligomer is favored when adduct radical Ⅱ-91 is more stable than starting radical R• derived from xanthate Ⅱ-89. Besides, the first two reactions also indicate that radical Ⅱ-91 is significantly more stable than radical Ⅱ-93.
Scheme 2.28 Different fates of N-vinyl pyrrolidone and N-vinyl phthalimide
To confirm this unanticipated observation, pyrrolidonyl and succinimidyl groups were set up in the xanthate part (Ⅱ-99 and Ⅱ-100). Now the effect is reversed (Scheme 2.29). The reaction of allylcyanide and pyrrolidonyl xanthate Ⅱ-99 gave mostly oligomers while succinimidyl xanthate 100 and phthalimidoyl xanthate 104 give the expected products 102 and Ⅱ-105. These results proved the fact that the pyrrolidone-substituted radical Ⅱ-103a is less stable than phthalimide- and succinimide-substituted radicals Ⅱ-106a. This speculation would be explained by the resonance structures below. The radical Ⅱ-106a has more allylic character than radical Ⅱ-103a.
31
Scheme 2.29 Stabilization effect of adjacent radicals by an imide group
2.6.5 Synthesis of protected amino acid derivatives
Reaction of amino acid bearing xanthates with various alkene coupling partners is a powerful strategy to produce various amino acids. Initiated by peroxide, NBS reacts with phthalimide protected amines to form brominated derivatives, which can be substituted with a xanthate salt to form the corresponding xanthate. Xanthate Ⅱ-107 was prepared in this manner and its addition to numerous alkenes, provides a convenient pathway to substituted protected β-amino acids Ⅱ-108a-f.43 It is worth pointing out the adduct Ⅱ-108d (Scheme 2.30) is the methyl ester of β-lysine which is produced by platelets during coagulation. It also has antibacterial activity by causing lysis of many Gram-positive bacteria by acting as a cationic detergent.44
Scheme 2.30 Synthesis of protected β-amino acids
Another protocol to synthesize amino acid derivatives is to set up an amino acid motif on the alkenes and introduce substituents through the xanthate partner. Adding various xanthates to enantiopure vinylglycine provides access to a series of non-racemic α-amino acids.45 Diverse functional groups such as nitrile Ⅱ-110a, tertiary butyl group Ⅱ-110b, ester Ⅱ-110c, and Weinreb amide Ⅱ-110d are all easily introduced. By using substituted α-ketonyl xanthates, various amino acids Ⅱ-110e-g can be rapidly produced which would otherwise be exceedingly tedious to obtain by conventional methods (Scheme 2.31).
32
Scheme 2.31 Synthesis of enantiopure α-amino acids
2.6.6 Modification of heterocycles
Heteroaromatic compounds are important constituents of drugs and bioactive molecules and are the focus of intense study by medicinal chemists.46 In addition to ionic chemistry, pathways to modify heterocycles based on the unique radical chemistry of xanthates constitute complementary approaches.
(i) Cyclization onto aromatic ring
Xanthates bearing an indole or benzothiophene ring Ⅱ-111a, b react smoothly with allyl acetate and result in the corresponding radical adduct Ⅱ-112a, b in good yields. This can be followed by reaction using a stoichiometric amount of lauroyl peroxide to furnish cyclized products Ⅱ-113a, b, respectively. The addition of xanthate Ⅱ-114 to allyl acetate gives adduct Ⅱ-115 which can cyclize in the next step to form isomers Ⅱ-116a and Ⅱ-116b containing a fused seven-membered ring. The combined yield of the two isomeric products is moderate, but the cyclization exhibits no regioselectivity. Tryptophan derivatives Ⅱ-118a-c could be obtained in similar yields from their xanthate precursors Ⅱ-117a-c under the same conditions (Scheme 2.32).47 The formation of seven-membered rings by direct radical cyclization onto aromatic and heteroaromatic rings is very rare. It is a slow process and difficult to accomplish by most radical methods. The examples in Scheme 2.32 further highlight the unique features of the xanthate-based technology.
33
Scheme 2.32 Xanthate-mediated annelations of seven-membered rings.
Bicyclic pyridine derivatives have been rapidly constructed by the xanthate route, including five, six, seven membered-rings (Scheme 2.32).48 For example, direct cyclization of xanthates Ⅱ-119 furnish 7-azaoxindoles Ⅱ-120a-d in good yields. In the synthesis of 7-azaindolines, a radical addition-cyclization sequence gives rise efficiently to the desired products Ⅱ-123a-c. Adding xanthate Ⅱ-124 onto allyl acetate resulted in the formation of radical adduct Ⅱ-125, which was closed into tetrahydro-5H-pyrido[2,3-b]azepin-8-ones Ⅱ-126 by the action of stoichiometric peroxide.
34
Scheme 2.33 xanthate route to pyridine-containing bicyclic products.
A concise route to a large number of azaindanes relies on the radical addition of substituted S-pyridylmethyl xanthates such as Ⅱ-127 and Ⅱ-131 to various alkenes and cyclization of the resulting adducts 128 and 132. The cyclizations leading to the respective azaindanes Ⅱ-129a-c and Ⅱ-133a-c required activating the pyridine ring by protonation with trifluoroacetic acid (Scheme 2.34).49
35
Scheme 2.34 Modular route to azaindanes (ii) Direct alkylation of heteroaromatic rings
Methyl and ethyl groups can be introduced indirectly via the carboxylic acid derived xanthates. The radical addition is followed by decarboxylation. Depending on the heteroarene structure, spontaneous or microwave assisted decarboxylation can be accomplished efficiently50 For example, exposure of caffeine Ⅱ-135 or pyrazine Ⅱ-139 to xanthate Ⅱ-136 in refluxing ethyl acetate using stoichiometric quantities of DLP added portion-wise provides the methylation products Ⅱ-138 and Ⅱ-140 directly. For other heteroarenes, incomplete or no decarboxylation was observed and the adducts had to be heated in a microwave oven to induce the elimination of carbon dioxide. Alkylated products Ⅱ-143a-f were obtained in this manner (Scheme 2.35).
36
Scheme 2.35 Direct alkylations of heteroarenes
The xanthate-mediated radical addition offers an alternative for introducing tert-butyl group into heteroaromatic rings. The starting xanthate Ⅱ-144 was synthesized under photolysis conditions51 and then added to various heterocycles to form the desired products Ⅱ-146a-f in moderate to good yields (Scheme 2.36).52
Scheme 2.36 Introduction of t-butyl groups by xanthate
2.7 Conclusion
37
studied the past three decades. Numerous applications of this methodology have been implemented including the addition to unactivated alkenes and the cyclization onto heteroarenes to afford complex heterocycles. Highly functionalized compounds can be accessed via inter or intramolecular alkylation that would be very tedious to perform with other methods. In the practical sense, this radical chemistry of xanthates features easily handled reaction conditions, low cost of starting materials, versatility, ease of scale-up and broad functional groups tolerance, especially polar groups that are often not compatible with conditions prevailing in ionic and organometallic reactions. The versatility of this xanthate chemistry opens up vast possibilities for the rapid synthesis of complex structures and the late-stage modification of natural products and drugs.
In this thesis, we have utilized these advantages for the synthesis of ketones and esters, β-amino acid derivatives as well as β-heteroarylethylamines.
